Abstract
Primary aldosteronism is one of the important causes of secondary hypertension. However, pregnancy with primary aldosteronism is rare. Eplerenone is an aldosterone antagonist which is used in the treatment of primary aldosteronism. This is a case of successful pregnancy outcome in a young woman who was known to have primary aldosteronism and was on oral eplerenone from preconception. There are only five case reports on eplerenone use during pregnancy in the literature.
Introduction
Primary aldosteronism is one of the common causes of secondary hypertension in the general population. 1 However, primary aldosteronism is rarely diagnosed during pregnancy. Physiologic changes in pregnancy result in the elevation of aldosterone and renin levels. This may cause a diagnostic dilemma during the evaluation of primary aldosteronism in pregnancy. Mineralocorticoid receptor antagonists such as spironolactone and eplerenone are the drugs of choice in treating primary aldosteronism in the general population. Spironolactone is contraindicated in pregnancy because it may lead to the feminisation of the male fetus. Eplerenone has a lower affinity for androgen receptors and the risk of feminisation of the male fetus is therefore likely to be lower. However, there is not much literature on the safety of this drug during pregnancy. This is a case report of a successful pregnancy outcome in a young woman who had primary aldosteronism and used eplerenone throughout the pregnancy.
Case
A 29-year-old woman in her first pregnancy presented in the first trimester. She had been diagnosed with primary aldosteronism two years prior to conception, during the evaluation of headache, and she was found to have high blood pressure (170/110 mmHg) and hypokalaemia. Renal ultrasound and Doppler were normal, and no proteinuria was present. Primary hyperaldosteronism was diagnosed with a plasma aldosterone concentration to plasma renin activity (PAC/PRA) ratio of 35.19 (normal <10), followed by a saline suppression test. Magnetic resonance imaging (MRI) of the abdomen and pelvis was normal, and a diagnosis of possible bilateral adrenal hyperplasia was made. She was advised to take oral spironolactone 25 mg twice daily and amlodipine. She had no family history of primary aldosteronism.
Spironolactone was replaced by oral eplerenone 25 mg twice daily and she conceived spontaneously. She continued to take oral eplerenone and amlodipine throughout pregnancy. The decision to continue this combination of drugs during pregnancy was taken as her blood pressure was well controlled, and other combinations of drugs had been tried before pregnancy and were ineffective in controlling her blood pressure. Aspirin (150 mg) was started at 12 weeks of gestation. Subclinical hypothyroidism (thyroid stimulating hormone – 6.21 µIU/ml) was diagnosed during her first trimester and oral levothyroxine 25 µg daily was started. Gestational diabetes mellitus was diagnosed at 20 weeks of gestation (using International Association of Diabetes and Pregnancy Study Groups criteria, 75 g glucose tolerance test), and she was advised about appropriate dietary changes. Fundoscopic examination and maternal echocardiography findings were normal. Her pregnancy was uneventful, and her blood sugars were well controlled. Her blood pressure was well controlled throughout pregnancy (Figure 1). At 36 weeks of gestation, she was found to have proteinuria (urine protein–creatinine ratio 45 mg/mmol) during a regular antenatal check-up, and superimposed preeclampsia was diagnosed. On admission, her blood pressure was 130/90 mmHg, and her investigations were normal except for elevated serum creatinine (91.9 µmol/L). An obstetric scan at 36 weeks detected fetal growth restriction (FGR) with an estimated fetal weight of 2 kg (4.4 percentile). Initial amniotic fluid index and Doppler studies were normal. Induction of labour was undertaken at 36 weeks and 3 days of gestation in view of FGR and abnormal cerebroplacental ratio (<1). A 2.1 kg male baby was delivered. The baby had normal external genitalia with no evidence of feminisation. The baby did not need Neonatal Intensive Care Unit care. Postnatally she was continued on the same medications, and her blood pressure was within normal limits. She had an uneventful postnatal period and got discharged on postnatal day 4. Currently, the baby is well and no developmental issues have been identified in the first year of life.
Graphical representation of blood pressure.
Discussion
Primary aldosteronism is one of the common causes of secondary hypertension in adults, with a prevalence of 20% in patients with resistant hypertension, 10% with severe hypertension, and 6% in those with uncomplicated hypertension. 1 Screening for primary aldosteronism is advised in adults with hypertension if one or more of the following criteria is fulfilled: hypertension with hypokalaemia, hypertension resistant to three antihypertensive drugs, hypertension with a family history of early-onset hypertension or cerebrovascular accident at a young age and hypertensive patients with a history of primary aldosteronism in a first-degree relative.1,2 In primary aldosteronism, there is increased aldosterone and suppressed renin; this can be due to aldosterone-producing adenoma (60%) or bilateral adrenal hyperplasia (40%). 2 High aldosterone levels will increase blood volume, cardiac output, and blood pressure.
Diagnosis during pregnancy is challenging because aldosterone and renin levels increase. PAC >10 ng/dL is considered abnormal in non-pregnant individuals. 3 However, a PAC/PRA ratio >40 and direct renin concentration under 20 mU/L during pregnancy are suggestive of primary aldosteronism. 4 Saline suppression tests for confirmation of the diagnosis are not advised in pregnancy due to the risk of volume expansion. 3 Ultrasound of the adrenal has not been found to be beneficial. 5 Computed tomography of the abdomen is generally contraindicated in pregnancy. MRI of the adrenals can distinguish between an adrenal adenoma and adrenal hyperplasia.
Primary aldosteronism may be associated with adverse pregnancy outcomes. In a literature review, Landau and Amar 5 identified 40 pregnancies in 38 women with primary aldosteronism. Blood pressure was not controlled in 32.3%, and six patients required an adrenalectomy during pregnancy. The adverse pregnancy outcomes included preeclampsia (23.8%), increased risk of caesarean section (44%), stillbirths (9.4%), and high prevalence of induced deliveries (61.2%). The median gestational age was 35.5 weeks, and the median birth weight was 2070 g. 5
The drug of choice for primary aldosteronism in non-pregnant individuals is a mineralocorticoid receptor antagonist such as spironolactone and eplerenone. 1 Spironolactone is generally contraindicated during pregnancy because it binds to testosterone and progesterone receptors and may lead to the feminisation of a male fetus. 6 Eplerenone is a spironolactone derivative that selectively binds to mineralocorticoid receptors and has only a low affinity for the androgen receptor. 2 The Australian Therapeutic Goods Administration has labelled eplerenone as category B3. Animal studies (rabbit and rat studies) have revealed decreased fetal weight, decreased maternal body weight, increased fetal resorption, and increased post-implantation loss at exposures up to 32 times the human area under the curve for the 100 mg/day therapeutic dose. There are no controlled data on human pregnancy. Only a few case reports are available, and in those studies, feminisation of male fetuses with eplerenone has not been reported. The starting dose is usually 25 mg twice daily and gradually titrated to the lowest effective dose.
Adrenalectomy is the surgical treatment for an adrenal adenoma. There are various case reports in which laparoscopic adrenalectomy was done during the second trimester of pregnancy, resulting in improved blood pressure after surgery. 7
In this case, primary aldosteronism was detected before pregnancy, and the patient was on oral eplerenone throughout pregnancy. She had a successful pregnancy outcome despite preeclampsia at 36 weeks, and the male baby was normally masculinised. Other case reports on the usage of eplerenone during pregnancy are shown in Table 1.
Review of literature on the use of eplerenone during pregnancy.
P = parity (number of live births + number of miscarriages or termination of pregnancy).
Conclusion
Management of primary aldosteronism during pregnancy needs a multidisciplinary team approach. Pregnancy outcome depends upon the control of blood pressure and associated complications. Eplerenone seems to be a safe drug in pregnancy, with no reports of feminisation of male fetuses. However, more studies and data are needed to confirm these findings.
Footnotes
Acknowledgements
None.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethical approval
The institution approves informed consent from the patients for case reports and case series. The institution does not mandate a separate ethical approval for reporting cases.
Informed consent
Informed written consent was obtained from patients.
Guarantor
Divya Mecheril Balachandran is the guarantor of the present work.
Contributorship
DMB, MS, and GD conceived the idea. DMB wrote the first manuscript and MS and GD revised and finalised the manuscript.
